A mentored clinical scientist career development award will enable me to continue developing as a physician scientist and become an independent investigator. I have the institutional support and protected time to develop my research career. I have identified two outstanding mentors for my career development award in George Eisenbarth and John Kappler. The goal of the proposed research project is to understand the immunologic mechanisms by which 'drug- like' small molecules can be used to block the underlying autoimmunity in major histocompatibility complex (MHC) class II restricted autoimmune diseases. The human MHC class II molecules DQ8 and DQ2 are the major determinants of both type 1 diabetes and celiac disease with more than 99% of patients with celiac disease having DQ8 or DQ2 and more than 90% of patients with type 1 diabetes have these alleles. By targeting MHC class II molecules, it is possible to use small molecules to block the presentation of autoantigens to T cells while other molecules can stimulate the production of protective cytokines (e.g. IL10). The first two aims of the proposal will evaluate compounds in the NOD mouse which is a spontaneous mouse model for autoimmune diabetes to understand how small molecules alter the presentation of autoantigens to CD4 T cells. Studies will be performed to both prevent and reverse diabetes onset. Follow up studies will be done to ensure the potential therapies are safe and do not abrogate normal immune system function. The final aim looks to evaluate small molecules targeted to the human MHC class II molecule DQ8. Initially in vitro studies will be done to evaluate small molecule response to CD4 T cells restricted to insulin (type 1 diabetes) and gliadin peptides (celiac disease) presented by DQ8. Those small molecules showing specificity and effectiveness in our initial assays will be tested using humanized transgenic mice that contain the DQ8 allele. If successful this proposal will lead to a proof of principle that small molecules targeted to human MHC class II molecules are capable of stimulating and inhibiting CD4 T cell responses to autoantigens and could potentially lead to a safe and specific class of immunotherapy. My overall career goal is to become an independent NIH-funded investigator applying the knowledge gained during my career development award period to better understand the underlying autoimmunity of MHC class II restricted autoimmune disorders and ultimately improve the clinical care for patients afflicted with these diseases.